Interferome profiling in the blood links IFNα5-Mucin-1 axis to HIV-1 pathogenesis

Type I interferons (IFN-Is) are essential for antiviral immunity, but contribute to immune dysfunction during chronic HIV-1 infection. IFN-Is comprise multiple IFNα subtypes that signal through a common receptor yet exhibit distinct biological activities, but their qualitative roles in HIV-1 pathogenesis remain incompletely defined. We previously identified IFNα5 as the dominant IFN-I in the systemic circulation of untreated people with HIV (PWH). Here, we delineated IFNα subtype-specific interferomes in peripheral blood mononuclear cells (PBMCs) from HIV-uninfected donors by transcriptomic profiling, and integrated these signatures with blood transcriptomes from untreated PWH, and matched controls. Although the IFN-Is tested induced canonical interferon-stimulated genes (ISGs) in vitro, they also induced different transcriptional programs. In vivo, dysregulation of multiple canonical ISGs, including CD38, LAG3, and CMPK2, correlated with plasma HIV-1 RNA levels, CD4 T-cell depletion, and/or systemic inflammatory markers. By contrast, the IFN-downregulated genes CXCL5 and VSIG4 were repressed in PWH and inversely correlated with viral load. Notably, MUC1, a non-canonical ISG that was most strongly induced by IFNα5, was significantly upregulated in PWH and associated with the inhibitory receptor LAG3, and markers of IL-6-driven inflammation. Flow cytometric analysis demonstrated increased Mucin-1 surface density on circulating CD4 T cells of PWH vs controls. Together, these findings demonstrate that IFNα subtypes can drive qualitatively distinct responses in bulk PBMC, identify IFNα5-associated gene programs in blood that may contribute to immune dysregulation among untreated PWH, and refine current models of IFN-I involvement in HIV-1 pathogenesis.IMPORTANCEPeople living with HIV experience persistent immune activation and inflammation that contribute to immune system damage and long-term health complications. Molecules known as type I interferons (IFN-Is) help control viruses early in infection, but prolonged exposure to these signals may also worsen immune dysfunction. Here, we show that IFNα5 is the dominant interferon present in the blood of people with untreated HIV and activates a distinct gene program in circulating immune cells. This program includes genes linked to immune activation, metabolic dysfunction, and immune exhaustion. IFNα5 strongly induces Mucin-1 on CD4 T cells, which is associated with systemic inflammation. These findings identify IFN pathways that may contribute to immune dysfunction during chronic HIV infection and highlight potential targets for restoring immune health.